We request funding for years 21 to 25 of a program project grant entitled ~Genetic Causes of Mental Retardation~. Study of adrenoleukodystrophy (ALD), which is associated with mental retardation, was part of the original application. Eleven years ago, ALD was shown to be a peroxisomal disorder, and at about the same time it was recognized that this disease category also includes disorder such as the Zellweger syndrome, in which mental retardation is even more frequent and severe. The connection between the peroxisomal abnormality and mental retardation. Knowledge about peroxisomal disorders is advancing rapidly. They are more common and varied than had been recognized in the past. Our clinic has identified the largest number of such patients known anywhere, and during the last five years this program project grant has focused on peroxisomal disorders exclusively. The present proposal includes five projects in addition to an administrative and molecular biology core. Subproject 0009 will study phenotype-0012 genotype correlations. Subproject 0012 will examine how defects of the recently identified ALD gene cause neurological damage and mental retardation. Subprojects and 0013 will study disorders of peroxisome assembly, such as the Zellweger syndrome, which can be caused by at least eleven distinct gene defects, three of which has been defined during the last three years. Project will focus on homologues of such assembly defects in yeast, in which the biologic mechanisms can be identified rapidly, and Project 0013 will focus on human mutants. The continuum from clinical to molecular and cell biology is the central theme of this program and provides its motivation and cohesion.